The adipocyte clock controls brown adipogenesis through the TGF-β and BMP signaling pathways

Deokhwa Nam, Bingyan Guo, Somik Chatterjee, Miao Hsueh Chen, David Nelson, Vijay K. Yechoor, Ke Ma

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

The molecular clock is intimately linked to metabolic regulation, and brown adipose tissue plays a key role in energy homeostasis. However, whether the cell-intrinsic clock machinery participates in brown adipocyte development is unknown. Here, we show that Bmal1 (also known as ARNTL), the essential clock transcription activator, inhibits brown adipogenesis to adversely affect brown fat formation and thermogenic capacity. Global ablation of Bmal1 in mice increases brown fat mass and cold tolerance, and adipocyte-selective inactivation of Bmal1 recapitulates these effects and demonstrates its cell-autonomous role in brown adipocyte formation. Further loss- and gain-of-function studies in mesenchymal precursors and committed brown progenitors reveal that Bmal1 inhibits brown adipocyte lineage commitment and terminal differentiation. Mechanistically, Bmal1 inhibits brown adipogenesis through direct transcriptional control of key components of the TGF-β pathway together with reciprocally altered BMP signaling; activation of TGF-β or blockade of BMP pathways suppresses enhanced differentiation in Bmal1-deficient brown adipocytes. Collectively, our study demonstrates a novel temporal regulatory mechanism in fine-tuning brown adipocyte lineage progression to affect brown fat formation and thermogenic regulation, which could be targeted therapeutically to combat obesity.

Original languageEnglish (US)
Pages (from-to)1835-1847
Number of pages13
JournalJournal of Cell Science
Volume128
Issue number9
DOIs
StatePublished - 2015

Keywords

  • Adipogenesis
  • Brown adipocyte differentiation
  • Circadian rhythm
  • Obesity
  • TGF-β signaling pathway

ASJC Scopus subject areas

  • Cell Biology

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